A mass spectrometry (MS) system in general includes an ion source for ionizing components of a sample of interest, a mass analyzer for separating the ions based on their differing mass-to-charge ratios (or m/z ratios, or more simply “masses”), an ion detector for counting the separated ions, and electronics for processing output signals from the ion detector as needed to produce a user-interpretable mass spectrum. Typically, the mass spectrum is a series of peaks indicative of the relative abundances of detected ions as a function of their m/z ratios. The mass spectrum may be utilized to determine the molecular structures of components of the sample, thereby enabling the sample to be qualitatively and quantitatively characterized.
A time-of-flight mass spectrometer (TOF MS) utilizes a high-resolution mass analyzer (TOF analyzer). Ions may be transported from the ion source into the TOF entrance region through a series of ion guides and ion lenses. The TOF analyzer includes an ion extractor (or pulser) that extracts ions in pulses (or packets) into an electric field-free flight tube. In the flight tube, ions of differing masses travel at different velocities and thus separate (spread out) according to their differing masses, enabling mass resolution based on time-of-flight.
Ions are pulsed out from the extractor at a certain frequency such as, for example, 5 to 20 kHz. A problem with this arrangement relates to the ions that arrive at the extractor between the extraction pulses. The velocity of the ions is such that many of them fly through the extractor long before the next pulse into the flight tube occurs, and as a result these ions are lost. That is, these ions are not injected into the flight tube and thus are not detected, and thus do not contribute to the ion signal utilized to produce a mass spectrum of the sample under analysis. This effect is often referred to as the “low duty cycle” associated with TOF acquisition.
Various methods have been taken to mitigate this effect. In one method, ions are trapped by ion optics preceding the TOF extractor. The trapped ions are released at specific points in time correlated with the extraction pulse sequence. While improving the duty cycle, this method suffers from problems such as reduced mass discrimination, reduced dynamic range, and trap space-charge limits.
Another family of techniques relies on multiplexing (or “multi-pulsing,” or “over-pulsing”). In these approaches, the frequency of extractions is increased significantly so that much more of the ions entering the TOF analyzer are extracted and hence much less of the ions are lost.
However, in these approaches there is an overlap between contiguous ion packets, which often contain a wide range of m/z ratios, and which may make mass assignment difficult or impossible. Proposed solutions to this problem attempt to “recover” the original spectra based on some kind of encoding of the pulsing sequence. For instance, the pulses may be triggered with certain pseudo-random delays that allow for the de-convolution of the resulting spectra. While reasonably good results have been demonstrated using such approaches, the de-convolution algorithms are not lossless and their effectiveness depends on the complexity of the original spectrum. For example, spectra from complex biological samples often contain very high densities of peaks and are a challenge for such approaches.
Another practical limitation stems from the fact that the TOF extractor has to be operated at a fairly high frequency (extraction pulse rate). For a relatively short flight tube a frequency of up to, for example, 50 kHz or more may be needed. Even more critically, if one wanted to change the acquisition mode from multiplexed to normal, a significant change in extraction frequency would be required. This would lead to a variation in the extractor output and, consequently, a loss of resolution and mass accuracy. As a result, recalibration, as well as a long settling period, would be required before the analysis is continued.
Therefore, there is a need for providing better control over ions pulsed into a TOF analyzer.